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[ CAS No. 89809-64-3 ] {[proInfo.proName]}

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Chemical Structure| 89809-64-3
Chemical Structure| 89809-64-3
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Product Details of [ 89809-64-3 ]

CAS No. :89809-64-3 MDL No. :MFCD03788835
Formula : C6H3ClN2 Boiling Point : No data available
Linear Structure Formula :- InChI Key :WTHODOKFSYPTKA-UHFFFAOYSA-N
M.W : 138.55 Pubchem ID :3833942
Synonyms :

Calculated chemistry of [ 89809-64-3 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 33.96
TPSA : 36.68 ?2

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.09 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.46
Log Po/w (XLOGP3) : 1.49
Log Po/w (WLOGP) : 1.61
Log Po/w (MLOGP) : 0.4
Log Po/w (SILICOS-IT) : 1.98
Consensus Log Po/w : 1.39

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.13
Solubility : 1.02 mg/ml ; 0.00739 mol/l
Class : Soluble
Log S (Ali) : -1.87
Solubility : 1.88 mg/ml ; 0.0136 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.7
Solubility : 0.278 mg/ml ; 0.002 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.77

Safety of [ 89809-64-3 ]

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

Application In Synthesis of [ 89809-64-3 ]

* 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 [ 89809-64-3 ]

[ 89809-64-3 ] Synthesis Path-Downstream   1~10

  • 1
  • [ 89809-64-3 ]
  • [ 84478-72-8 ]
  • 5-(5-amino-2-chloro-4-fluorophenoxy)picolinonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium tert-butylate; In ISOPROPYLAMIDE; at 80℃; Example A16 A solution of <strong>[84478-72-8]5-amino-2-chloro-4-fluorophenol</strong> (100 mg, 0.619 mmol) in degassed dimethylacetamide (2 mL) was treated with potassium t-butoxide (83 mg, 0.743 mmol) and 5-chloro-2-cyanopyridine (86 mg, 0.619 mmol). The resultant mixture was heated to 80 C. overnight, then cooled to RT and diluted with water (10 mL). The mixture was extracted with EtOAc (30 mL). The organic phase was washed with water (3*30 mL) and brine (30 mL) dried (Na2SO4) and concentrated in vacuo to provide 5-(5-amino-2-chloro-4-fluorophenoxy)picolinonitrile as a dark oil which was used without further purification. MS (ESI) m/z: 264.0 (M+H+).
With potassium tert-butylate; In N,N-dimethyl acetamide; at 80℃; A solution of <strong>[84478-72-8]5-amino-2-chloro-4-fluorophenol</strong> (100 mg, 0.619 mmol) in degassed dimethylacetamide (2 mL) was treated with potassium t- butoxide (83 mg, 0.743 mmol) and 5-chloro-2-cyanopyridine (86 mg, 0.619 mmol). The resultant mixture was heated to 80 C overnight, then cooled to RT and diluted with water (10 mL). The mixture was extracted with EtOAc (30 mL). The organic phase was washed with water (3 x 30 mL) and brine (30 mL) dried (Na2SC>4) and concentrated in vacuo to provide 5-(5-amino-2-chloro-4-fluorophenoxy)picolinonitrile as a dark oil which was used without further purification. MS (ESI) m/z: 264.0 (M+H+).
  • 2
  • [ 89809-64-3 ]
  • [ 327056-62-2 ]
YieldReaction ConditionsOperation in experiment
72% In 1-methyl-pyrrolidin-2-one; at 210 - 220℃; for 4h; Preparation 84; 2-Cyano-5-fluoropyridine; Add in a 5-L 3-neck roundbottom equipped with overhead stirrer, reflux condenser, thermometer, and N2 line, 5-chloro-2-cyanopyridine (193.0 g, 1. 39 mol) and 1-methyl-2-pyrrolidinone (NMP, 2L). Heat the mixture and stir at 210-220 C for 4 h. Cool the reaction mixture to room temperature, stir overnight, and filter. Wash the filter cake with ethyl ether (1L). Extract the filtrate with water (6L) and ethyl ether (3 X 5L). Combine the organics and back-extract with water (8L) and dry over magnesium sulfate. Concentrate at 25-30 C to give an oily semi-solid, 193 g. Chromatograph over flash silica gel (5% ethyl acetate in hexanes gradually increasing to 10% ethyl acetate in hexanes) to provide the title compound as a white solid. Dissolve the solid in ethyl ether, filter, and add hexanes. Concentrate to low volume to provide a primary crop of pure title compound, 60 g. Repeat the process of crystallization on the filtrate to provide a second crop of highly pure title compound, 24.0 g. (Concentrate the final filtrate to a white solid of product of good quality, and re-chromatograph, conditions as above, to provide an additional 38.6 g of material. ) Obtain a total yield of title compound of 122.4 g, 72% ; 1H NMR (CDCl3) 5 8.59 (d, J= 3.0 Hz, 1H), 7.75 (m, 1H), 7.55 (m, 1H).
425 mg (48%) With potassium fluoride; In 1-methyl-pyrrolidin-2-one; A mixture of 2-cyano-5-chloropyridine (1 g, 7.22 mmol) and potassium fluoride (1.26 g, 21.68 mmol) in 1-methyl-2-pyrrolidinone (25 mL) was heated at reflux for 18 hours. After cooling, the reaction was diluted with ethyl acetate and extracted with water and brine. The organic solvents were then removed in vacuo. Silica gel chromatography of the residue afforded 425 mg (48%) of 2-cyano-5-fluoropyridine.
  • 3
  • [ 89809-64-3 ]
  • [ 67938-76-5 ]
YieldReaction ConditionsOperation in experiment
51% With hydrogenchloride; hydrogen;palladium 10% on activated carbon; In ethanol; water; under 2068.65 Torr; for 2.0h; A solution of 5-chloropicolinonitrile (3.8 g, 27.43 mmol), conc. HCl (3 mL) and 10percent Pd-C (1.0 g) in ethanol (100 mL) was shaken under a hydrogen atmosphere (40 psi) for 2 h. The reaction mixture was filtered, concentrated and the resulting residue taken up in satd NaHCO3 (50 mL) and extracted with CH2Cl2 (4x25 mL). The combined CH2Cl2 layers were dried (Na2SO4), filtered and concentrated to give the title compound as a yellow oil (2.0 g, 51percent yield). LCMS (M+H) calcd for C6H8ClN2: 143.04; found: 143.07. 1HNMR (500 MHz, CDCl3) ? ppm: 8.56-8.51 (1H, br d), 7.66-7.60 (1H, m), 7.28-7.14 (1H, m), 3.97 (2H, s), 1.72 (2H, s).
51% With hydrogenchloride; hydrogen;palladium 10% on activated carbon; In ethanol; water; under 2068.65 Torr; for 2.0h; A solution of 5-chloropicolinonitrile (3.8 g, 27.43 mmol), conc. HCl (3 mL) and 10percent Pd-C (1.0 g) in ethanol (100 mL) was shaken under a hydrogen atmosphere (40 psi) for 2 h. The reaction mixture was filtered, concentrated and the resulting residue taken up in satd NaHCO3 (50 mL) and extracted with CH2Cl2 (4.x.25 mL). The combined CH2Cl2 layers were dried (Na2SO4), filtered and concentrated to give the title compound as a yellow oil (2.0 g, 51percent yield). LCMS (M+H) calcd for C6H8ClN2: 143.04; found: 143.07. 1HNMR (500 MHz, CDCl3) delta ppm: 8.56-8.51 (1 H, br d), 7.66-7.60 (1 H, m), 7.28-7.14 (1 H, m), 3.97 (2H, s), 1.72 (2H, s).
51% With hydrogenchloride; hydrogen;palladium 10% on activated carbon; In ethanol; water; under 2068.65 Torr; for 2.0h; (5-Chloropyridin-2-yl)methanamine. A solution of 5-chloropicolinonitrile (3.8 g, 27.43 mmol), conc. HCl (3 mL) and 10percent Pd-C (1.0 g) in ethanol (100 mL) was shaken under a hydrogen atmosphere (40 psi) for 2 h. The reaction mixture was filtered, concentrated and the resulting residue taken up in satd NaHCO3 (50 mL) and extracted with CH2Cl2 (4.x.25 mL). The combined CH2Cl2 layers were dried (Na2SO4), filtered and concentrated to give the title compound as a yellow oil (2.0 g, 51percent yield). LCMS (M+H) calcd for C6H8ClN2: 143.04. found: 143.07. 1HNMR (500 MHz, CDCl3) delta ppm: 8.56-8.51 (1H, br d), 7.66-7.60 (1H, m), 7.28-7.14 (1H, m), 3.97 (2H, s), 1.72 (2H, s).
51% (5-Chloropyridin-2-yl)methanamine. A solution of 5-chloropicolinonitrile(3.8 g, 27.43 mmol), cone. HCl (3 mL) and 10percent Pd-C (1.0 g) in ethanol (100 mL) was shaken under a hydrogen atmosphere (40 psi) for 2h. The reaction mixture was filtered, concentrated and the resulting residue taken up in satd NaHCO3 (50 mL) and extracted with CH2Cl2 (4 X 25 mL). The combined CH2Cl2 layers were dried <n="142"/>(Na2SO4), filtered and concentrated to give the title compound as a yellow oil (2.0 g, 51percent yield). LCMS (M+H) calcd for C6H8ClN2: 143.04; found: 143.07. 1HNMR (500 MHz, CDCl3) delta ppm: 8.56-8.51 (IH, br d), 7.66-7.60 (IH, m), 7.28-7.14 (IH, m), 3.97 (2H, s), 1.72 (2H, s).

  • 4
  • [ 130723-13-6 ]
  • [ 89809-64-3 ]
  • [ 6921-34-2 ]
  • [ 939039-26-6 ]
YieldReaction ConditionsOperation in experiment
56% EXAMPLE 1; N-(l-(5-chloropyridin-2-yl)-l-(3-fluoro-5-(trifluoromethyl)phenyl)-2- phenylethyl)-4-(trifluoromethyl)thiazol-2-amine; Procedure 1; [00187] A dry 250 mL round bottomed flask was equipped a stirring bar and fitted to an adapter connected to the vacuum line. The flask was dried under vacuum and then purged several times with nitrogen. Under a stream of nitrogen, l-bromo-3- fluoro-5-(trifluoromethyl)benzene (2.5g, lOJmmoles) was added to the flask and dissolved in anhydrous ether (100 mL). The flask was fitted with a septum which was connected to the nitrogen line via a 16 gauge IV2 PrecisionGlide needle. The stirring solution was cooled to -78C for 10 minutes, n-BuLi (1.6M in hexanes, 6.4 mL. 10.3mmoles) was added drop wise. After 15 minutes, a solution of 5-chloro-2- cyanopyridine (1.42g, 10.3mmoles) in anhydrous THF (10 mL) was added from a syringe. The reaction was stirred for 2 hours at -78C and trimethylchlorosilane (1.41 mL, 10.3 mmoles) was added. The reaction vessel was removed from the acetone/dry ice bath and the reaction was allowed to warm up to room temperature. After 30 minutes, the reaction vessel was cooled to -78C, Benzylmagnesium chloride (2.0M in THF, 5.15 mL, 10.3 mmoles) was added and the reaction was allowed to slowly warm to room temperature for 2h. The reaction was quenched with H2O (10 mL). The crude product was poured into 200 mL ethyl acetate in a 1000 mL separatory <n="168"/>funnel. The light brown solution was washed with saturated aqueous NH4Cl (3 x 100 mL), then with water (2 x 100 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel ISCO with 95-75% hexanes in ethylacetate to yield 1- (5-chloropyridin-2-yl)-l-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine 994mg (24% yield). LC-MS (methanol) [MH] = 394.1H NMR (500 MHz, CDO3) delta ppm 8.58 (1 H, d, /=2.75 Hz), 7.57 - 7.64 (2 H, m), 7.45 (2 H, d, J=8.25 Hz), 7.09 - 7.24 (4 H, m), 6.81 (2 H, d, J=6.60 Hz), 3.93 (1 H, d, J=13.20 Hz), 3.46 (1 H, d, J=13.20 Hz), 1.87 (2 H, broad s).
  • 5
  • [ 130723-13-6 ]
  • [ 89809-64-3 ]
  • [ 939039-44-8 ]
YieldReaction ConditionsOperation in experiment
EXAMPLE 79; 2-(5-chloropyridin-2-yl)-2-(4,5-dimethylthiazol-2-ylamino)-2-(3-fluoro-5- (trifluoromethyl)phenyl)acetonitrile; Procedure 17; [00218] At -74 C to a solution of l-bromo-3-fluoro-5-(trifluoromethyl)benzene (11 g, 45.2 mmol) in ether (200 niL) was added dropwise n-BuLi (20 mL, 2.5 M in hexane, 49.8 mmol). The reaction mixture was stirred at -74 0C for 2 h. A solution of 5-Cl-2-cyanopyridme (6.23 g, 45.2 mmol) in THF (100 mL) was added to the reaction mixture via cannulation. The yellow brown reaction solution turned into dark. The reaction mixture was quenched by the addition of dry MeOH at -70 0C and then allowed to warm up to room temperature. The reaction mixture was concentrated to a small volume, filtered and the solid was separated and rinsed with ether. The combined filtrates were concentrated to yield (5-chloropyridin-2-yl)(3- fluoro-5-(trifluoromethyl)phenyl)methanimine as a black oil. LCMS RT = 3.913 min [M+H] 303.95 (Phenomenex Luna C18 column, 4.6 x 50 mm eluting with 10-90% MeOETH2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm)
  • 6
  • [ 130723-13-6 ]
  • [ 89809-64-3 ]
  • [ 939039-29-9 ]
YieldReaction ConditionsOperation in experiment
75% EXAMPLE 2; (S)-N-(l-(5-chloropyridin-2-yl)-l-(3-fluoro-5-(trifluoromethyl)phenyl)-2- phenylethyl)-4-(trifluoromethyl)thiazol-2-amine; Procedure 3; [00193] At -780C under Ar a dry 25OmL 3 neck flask was charged with l-bromo-3- fluoro-5-(trifluoromethyl)benzene (4.5g, 0.018mol). Dry ether (10OmL) was added and to the stirred solution, nBuLi (9.2mL, 0.018mol) was added dropwise via airtight syringe through a rubber septum. The resulting pale orange colored solution was stirred at -780C for 30 min. 5-chloropicolinenitrile (2.5g, 0.018mol) was then added as a thick slurry in dry ether (approx 1OmL) via wide neck tunnel. The resulting solution turned dark red in color and was stirred at -780C for 1 hr. LCMS indicated that the reaction was complete and, at -780C the reaction mixture was quenched with l.OM HCl (approx 5OmL). The cooling bath was removed and as the reaction mixture reached ambient temperature, (220C), the organic solution turned pale green in color. The solution was transferred to a separation funnel and the organic layer separated. The aqueous phase was washed with EtOAc (2OmL) and the combined organic portions dried over anhydrous Na2SO4, decanted and concentrated yielding a pale brown oil. This was dissolved in hexane (ca 15mL) and loaded directly onto a silica gel ISCO cartridge (33Og, previously equilibrated with hexanes) and elution at 100 mL/min gradient 0 to 70% EtOAc in hexanes over 45 min. Elution time of the product was 17 to 20mins and (5-chloropyridm-2-yl)(3-fluoro-5- (trifluoromethyl)phenyl)methanone (4.1g, 75% yield) was isolated as a pale yellow oil which crystallized on standing. Rf 0.74 (Hexane:EtOAc 4:1) LCMS: 2.03 min [M+l] 304.2 (2min gradient, MeOH/H2O 0.1%TFA); HPLC: 3.98 min (4min gradient, MeOH/H2O 0.2%PPA Purity 98%; NMR: 400MHz 1H (CDCl3) 8.69 ppm, IH, d, J=2.64Hz; 8.22 ppm, IH, s; 8.13 ppm, IH, d, J=8.36Hz; 8.07 ppm, IH, brd, J=8.4Hz; 7.93 ppm, IH, dd, J=2.2 and J=8.36Hz; 7.57 ppm, IH, brd, J=8.4Hz.
75% At -78 C under argon, to <strong>[130723-13-6]1-bromo-3-fluoro-5-(trifluoromethyl)benzene</strong> (4.5 g, 0.018 mol) in ether (100 mL) was added n-BuLi (9.2 mL, 0.018 mol) dropwise. The resulting solution was stirred at -78 C for 30 min. 5-Chloropicolinenitrile (2.5 g, 0.018 mol) was then added as a slurry in ether (10 mL) and the solution stirred at -78 C for 1 h then quenched with 1 M HCl. The reaction mixture was extracted with EtOAc and the organic portions were combined, dried over anhydrous Na2SO4, filtered, and concentrated. Yielded a pale brown oil, which was purified by flash chromatography to give 7 (4.1 g, 75%). 1H NMR (400 MHz, CDCl3) delta 8.69 (d, J=2.64 Hz, 1H), 8.22 (s, 1H), 8.13 (d, J=8.36 Hz, 1H), 8.07 (d, J=8.40 Hz, 1H), 7.93 (dd, J=8.36, 2.20 Hz, 1H), 7.57 (d, J=8.40 Hz, 1H), 4.05 (s, 3H), 3.30 (s, 3H), 1.61 (s, 9H). 19F NMR (376 MHz, CDCl3) delta -63.23, -109.82. 13C NMR (101 MHz, CDCl3) delta 189.0, 161.9 (d, J=276 Hz), 151.5, 147.7, 138.8 (d, J=8.6 Hz), 137.2, 136.3, 132.9 (dm, J=48.9 Hz), 125.9, 123.8 (m), 121.5 (d, J=28.6 Hz), 116.9 (dm, J=35.3 Hz). LC-MS (M+1)+=303.9. HRMS (ESI) calcd for C13H7ClF4NO (M+H)+=304.01468, found 304.01587.At rt, 7 (0.17 g, 0.60 mmol) was dissolved in THF (10 mL) and (R)-(+)-2-methylpropane-2-sulfinamide (0.072 g, 0.60 mmol) and Ti(OEt)4 (0.19 mL, 0.90 mol) were added. The solution was heated to 75 C for 14 h then cooled, concentrated under vacuum to half the volume, and purified by flash chromatography to yield 8 (40 mg, 31%). 1H NMR (400 MHz, CDCl3) (two sets of peaks attributed to E/Z isomerism) delta 8.62 (d, J=2.20 Hz, 1H), 8.22 (s, 1H), 8.46 (br s, 1H), 8.18 (d, J=8.00 Hz, 1H), 8.13 (d, J=8.00 Hz, 1H), 8.02 (d, J=8.00 Hz, 1H), 7.91 (br s, 1H), 7.82 (d, J=8.00 Hz, 1H), 7.74 (d, J=8.00 Hz, 1H), 7.68 (d, J=8.00 Hz, 1H), 7.51 (br m, 1H), 1.37 (s, 9H), 1.28 (s, 9H). 19F NMR (376 MHz, CDCl3) delta -63.75, -109.56. 13C NMR (101 MHz, CDCl3) delta 188.5, 161.8 (d, J=370 Hz), 151.4, 148.5, 147.7, 138.8 (d, J=19.4 Hz), 137.4, 136.0 (m), 125.8, 123.7 (m), 121.4 (m), 116.9 (dm, J=30.6 Hz), 59.0, 55.4, 22.9, 22.1. HPLC purity 96%, tR=10.51 min (60%) and 10.68 min (36%) (method E17); 94%, tR=9.04 min (59%) and 9.19 min (35%) (method F17). LC-MS (M+1)+=406.9. HRMS (ESI) calcd for C17H16ClF4N2OS (M+H)+=407.06025, found 407.06221.At -78 C under argon, LDA (2.0 M in heptane/THF, 3.69 mL, 7.39 mmol) was added to a solution of methyl acetate (547 mg, 7.39 mmol) in ether (40 mL) dropwise. After 30 min, Ti(i-OPr)3Cl (2.64 mL, 11.1 mmol) was added and the reaction mixture stirred for a further 30 min. In a separate flask, Ti(i-OPr)3Cl (0.88 mL, 3.69 mmol) was added under argon to a solution of 8 (1.50 g, 3.69 mmol) in ether (40 mL) at rt. After 30 min, this solution was cannulated dropwise into the solution of enolate under argon at -78 C. The mixture was stirred for 1 h then quenched at -78 C with saturated NaCl. Aqueous HCl (1.0 M, 20 mL) was subsequently added and the solution extracted with EtOAc, dried over Na2SO4, decanted, and concentrated. The resulting oil was purified by flash chromatography to yield an off-white solid (1.51 g, 85%). NMR analysis indicated a 92:8 ratio of (S)-methyl 3-(5-chloropyridin-2-yl)-3-((R)-1,1-dimethylethylsulfinamido)-3-(3-fluoro-5-(trifluoromethyl)phenyl)propanoate to (R)-methyl 3-(5-chloropyridin-2-yl)-3-((R)-1,1-dimethylethylsulfinamido)-3-(3-fluoro-5-(trifluoromethyl)phenyl)propanoate. The solid was dissolved in MeOH (5 mL) then added two drops of water and the solution cooled to 4 C for 2.5 h. Yielded pure (S)-methyl 3-(5-chloropyridin-2-yl)-3-((R)-1,1-dimethylethylsulfinamido)-3-(3-fluoro-5-(trifluoromethyl)phenyl)propanoate (1.04 g, 69%) as colorless needles. 1H NMR (400 MHz, CDCl3) delta 8.54 (d, J=2.2 Hz, 2H), 7.62 (dd, J=8.6, 2.4 Hz, 2H), 7.46-7.33 (m, 4H), 7.30-7.13 (m, 5H), 6.11 (s, 2H), 3.98 (d, J=17.4 Hz, 2H), 3.73 (d, J=17.4 Hz, 2H), 3.59 (s, 6H), 1.31 (s, 18H), 0.00 (s, 1H). 19F NMR (376 MHz, CDCl3) delta -62.81, -109.49. 13C NMR (101 MHz, CDCl3) delta 172.5, 162.4 (d, J=327 Hz), 158.1, 148.2 (d, J=8.4 Hz), 147.5, 136.6, 132.9 (dm, J=44.4 Hz), 131.6, 124.9, 118.7, 117.4 (d, J=22.1 Hz), 112.3 (dq, J=30.6, 6.7 Hz), 66.0, 57.1, 51.9, 43.7, 22.9. HPLC purity: 95%, tR=10.30 min (method E); 98%, tR=8.95 min (method F). LC-MS (M+H)+=480.9. HRMS (ESI) calcd for C20H22ClF4N2O3S (M+H)+=481.09703, found 481.09907. (S)-Methyl 3-(5-chloropyridin-2-yl)-3-((R)-1,1-dimethylethylsulfinamido)-3-(3-fluoro-5-(trifluoromethyl)phenyl)propanoate (110 mg, 0.23 mmol) was dissolved in methanol (2 mL), HCl in dioxane (4 M, 1 mL) was added and stirred for 30 min. The solution was diluted with DCM and aqueous NaOH (1 M) was added until the pH of the solution was 10. The organic phase was dried over Na2SO4, decanted, and concentrated to yield 9a as solid (84 mg). 1H NMR (400 MHz, CDCl3) delta 8.47 (d, J=1.9 Hz, 1H), 7.62 (dd, J=8.4, 2.5 Hz, 2H), 7.46 (dd, J=20.7, 9.3 Hz, 2H), 7.17 (d, J=8.1 Hz, 1H), 3.71-3.55 (m, 3H), 3.19 (d, J=16.5 Hz, 2H), 2.66 (s, 2H). 13C NMR (101 MHz, CDCl...
  • 7
  • [ 130723-13-6 ]
  • [ 89809-64-3 ]
  • [ 89523-63-7 ]
  • [ 939039-26-6 ]
YieldReaction ConditionsOperation in experiment
56% Alternate benzylzinc bromide procedure; [00189] A dry 200 mL round bottomed flask was equipped a stirring bar and fitted to an adapter connected to the vacuum line. The flask was dried under vacuum and then purged several times with nitrogen. Under a stream of nitrogen, l-bromo-3- fluoro-5-(trifluoromethyl)benzene (972mg, 4mmoles) was added to the flask and dissolved in anhydrous ether (75 mL). The flask was fitted with a septum which was connected to the nitrogen line via a 16 gauge lV2 PrecisionGlide needle . The stirring solution was cooled to -78C for 10 minutes, n-BuLi (1.6M in hexanes, 2.25 mL. 3.6mmoles) was added drop wise. After 15 minutes, a solution of 5-chloro-2- cyanopyridine (552mg, 4mmoles) in anhydrous THF (5 mL) was added from a syringe. The reaction was stirred for 2 hours at -78C and trimethylchlorosilane (550muL, 4mmoles) was added. The reaction vessel was removed from the acetone/dry ice bath and the reaction was allowed to warm up to room temperature. After 30 minutes, the reaction vessel was cooled to -780C, Benzylzinc chloride (0.5M in THF, 9.6 mL, 4.8 mmoles) was added and the reaction was allowed to slowly warm to room temperature for 3h. The reaction was quenched with H2O (1O mL). The crude product was poured into 200 mL ethyl acetate in a 1000 mL separatory funnel. The <n="169"/>light brown solution was washed with saturated aqueous NH4Cl (3 x 100 niL), then with water (2 x 100 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified on SCX column (1Og, high load, 0.65mmole/g) to yield l-(5-chloropyridin-2-yl)-l-(3-fluoro-5- (trifluoromethyl)phenyl)-2-phenylethanamine 890mg (56% yield). LC-MS (methanol) [M+l] = 394.
  • 8
  • [ 130723-13-6 ]
  • [ 7647-01-0 ]
  • [ 89809-64-3 ]
  • [ 939039-29-9 ]
YieldReaction ConditionsOperation in experiment
75% At -78 C. under Ar a dry 250 ml 3 neck flask was charged with <strong>[130723-13-6]1-bromo-3-fluoro-5-(trifluoromethyl)benzene</strong> (4.5 g, 0.018 mol). Dry ether (100 mL) was added and to the stirred solution, nBuLi (9.2 mL, 0.018 mol) was added dropwise via airtight syringe through a rubber septum. The resulting pale orange colored solution was stirred at -78 C. for 30 min. 5-chloropicolinenitrile (2.5 g, 0.018 mol) was then added as a thick slurry in dry ether (approx 10 mL) via wide neck funnel. The resulting solution turned dark red in color and was stirred at -78 C. for 1 hr. LCMS indicated that the reaction was complete and, at -78 C. the reaction mixture was quenched with 1.0M HCl (approx 50 mL). The cooling bath was removed and as the reaction mixture reaction reached ambient temperature, (22 C.), the organic solution turned pale green in color. The solution was transferred to a separation funnel and the organic layer separated. The aqueous phase was washed with EtOAc (20 mL) and the combined organic portions dried over anhydrous Na2SO4, decanted and concentrated yielding a pale brown oil. This was dissolved in hexane (ca 15 mL) and loaded directly onto a silica gel ISCO cartridge (330 g, previously equilibrated with hexanes) and elution at 100 mL/min gradient 0 to 70% EtOAc in hexanes over 45 min. Elution time of the product was 17 to 20 mins and (5-chloropyridin-2-yl)(3-fluoro-5-(trifluoromethyl)phenyl)methanone (4.1 g, 75% yield) was isolated as a pale yellow oil which crystallized on standing. Rf0.74 (Hexane:EtOAc 4:1) LCMS: 2.03 min [M+1] 304.2 (2 min gradient, MeOH/H2O 0.1% TFA); HPLC: 3.98 min (4 min gradient, MeOH/H2O 0.2% PPA Purity 98%; NMR: 400 MHz 1H (CDCl3) 8.69 ppm, 1H, d, J=2.64 Hz; 8.22 ppm, 1H, s; 8.13 ppm, 1H, d, J=8.36 Hz; 8.07 ppm, 1H, brd, J=8.4 Hz; 7.93 ppm, 1H, dd, J=2.2 and J=8.36 Hz; 7.57 ppm, 1H, brd, J=8.4 Hz.
  • 9
  • [ 130723-13-6 ]
  • [ 89809-64-3 ]
  • [ 75-77-4 ]
  • C16H15ClF4N2Si [ No CAS ]
YieldReaction ConditionsOperation in experiment
General procedure: Aryl or heteroaryl bromide (4 mmol) was charged in oven dried Radley's synthesis tube that was equipped with a stir bar under a stream of nitrogen. Anhydrous diethyl ether was added and the reaction mixture was cooled to -78 C. n-BuLi (1.6 M in hexanes, 2.5 mL, 4.00 mmol) was added dropwise and the reaction mixture was stirred at -78 C for 10 min. A solution of aryl or heteroaryl nitrile in THF (4 mmol) was added dropwise and the reaction mixture was stirred at -78 C for 2 h. TMSCl (0.550 mL, 4.00 mmol) was added to the reaction mixture at -78 C and the reaction mixture was allowed to warm up to 0 C. The reaction mixture was cooled to -78 C, benzylmagnesium chloride in either THF or ether (2 mmol) or benzyl zinc(II) bromide in ether (2 mmol), was added dropwise, stirred at -78 C for 2 h, and then stirred at rt for 12 h. The reaction mixture was worked up and purified as in general procedure 1.
  • 10
  • [ 89809-64-3 ]
  • [ 10177-24-9 ]
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; ;