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Product Details of [ 304694-40-4 ]

CAS No. :304694-40-4
Formula : C20H25F3N2
M.W : 350.42
SMILES Code : FC(C1=CC=C(C2=CC=C(CNCCN(CC)CC)C=C2)C=C1)(F)F
MDL No. :MFCD20926162

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Application In Synthesis of [ 304694-40-4 ]

* 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 [ 304694-40-4 ]

[ 304694-40-4 ] Synthesis Path-Downstream   1~2

  • 1
  • [ 304694-40-4 ]
  • [ 356058-42-9 ]
  • N-[2-(diethylamino)ethyl]-2-(2-[(4-fluorophenyl)methyl]thio}-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl)-N-[4’-(trifluoromethyl)-4-biphenylyl]methyl}acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
82.63% With boric acid; In toluene; at 110℃; for 6h; Example 9: Preparation of darapladib Toluene (400 mL) and NN-diethyl-N'-{ [4'-(trifluoromethyl)biphenyl-4- yl]methyl} ethane- 1,2-diamine (Formula 2; 50 g) were mixed in a round bottom flask at 25C and stirred. {2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH- cyclopenta[d]pyrimidin-l-yl}acetic acid (Formula 1; 50g), boric acid (4.45 g), and trifluoromethyl phenyl boronic acid (2.71 g) were added to the reaction mixture at 25C. The temperature of the reaction mixture was raised to 110C and refluxed for 6 hours. The reaction mixture was monitored by HPLC until the reaction was completed. The reaction mixture was cooled to 25C and a 5% NaOH solution (350 mL) was added, and then the mixture was stirred for 30 minutes at 25C. The reaction mixture was allowed to settle, and then the organic layer was collected. The organic layer was washed with water (200 mL), and then toluene was recovered completely under vacuum at 50C to obtain an oily residue. Methanol (350 mL) was added to the oily residue at 50C, and the mixture was stirred for 15 minutes. The reaction mixture was cooled to 25 C, then the solid was precipitated out, then water (200 mL) was added, and the mixture was stirred for 4 hours at 25 C. The solid was filtered, and then washed with a mixture of methanol (75 mL) and water (25 mL). The wet solid was unloaded, then dried under vacuum at 45 C for overnight to obtain the title compound. Yield: 78.60 (82.63%) Chemical Purity (by HPLC): 97.89%
78% With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 50℃; for 3h; Compound 2 (0.0100g, 0.03 mmol, 1 eq), compound 3 (0.0105 g, 0.03 mmol, 1 eq), 1-hydroxy-7-azabenzotriazole (HOAt) (0.0049 g, 0.036 mmol, 1.2 eq) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (0.0070 g, 0.045 mmol, 1.5 eq) was stirred in DMF (0.1 mL) for 3 hours at 50 C. The reaction was diluted in ethyl acetate, washed with saturated aqueous NaHCO3, dried over Na2SO4 and filtered. The solvent was removed by rotary evaporation and the product was purified by preparative thin-layer chromatography (10% methanol in dichloromethane) to afford darapladib (0.0156 g, 0.023 mmol, 78%).
65% General procedure: the appropriate amine (1 eq) and acid (1 eq) were dissolved in DMF (0.1 M) then stirred with DIPEA (2 eq) for 10 min at RT. The reaction was then cooled with an ice bath to 0C and COMU (1 eq) was added. The mixture was stirred at 0C for 1h then the bath was removed and the reaction was allowed to reach RT and continued for 5h. The compound was extracted using EtOAc three times. The combined organic layers were then washed several times with saturated NaHCO3. The resulting organic solution was dried, filtered and evaporated. The product was then purified using column chroma-tography with appropriate conditions indicated below.
65% With 1-[(1-(cyano-?2-?ethoxy-?2-?oxoethylidenaminooxy)?dimethylamino-?morpholino)]-uronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 6h;Inert atmosphere; Amine 8 (1 eq, 52 mg) and acid 12' (1 eq, 50 mg) were dissolved in DMF (1 mL) then stirred with DIPEA (2 eq, 52 mu) for 10 min at rt. The reaction was then cooled with an ice bath to 0C and COMU (1 eq, 64 mg) was added. The mixture was stirred at 0C for lh then the bath was removed and the reaction was allowed to reach rt and continued for 5h. The compound was extracted using EtOAc three times (5 mL x 3). The combined organic layers were then washed several times with saturated NaHC03 until washing solution was colourless. The resulting organic solution was dried, filtered and evaporated. The product was then purified using column chromatography on silica gel DCM/MeOH (90/10) (Rf = 0.2) as a pale yellow solid (65 mg, 65%). 1H NMR (600 MHz, CDC13) Mix of rotamers ratio (1/1) delta 7.69 (d, J = 7.9 Hz, 2H), 7.62 (d, J = 7.9 Hz, 1H), 7.56 (d, J = 6.7 Hz, 1H), 7.46 (m, 2H), 7.37-7.26 (m, 4H), 6.96 (t, J = 7.4 Hz, 1H), 6.89 (t, J = 7.4 Hz, 1H), 4.95 (s, 1H), 4.69 (m, 3H), 4.50 (s, 1H), 4.40 (s, 1H), 3.64 (m, 1H), 3.30 (m, 1H), 2.88 (m, 1H), 2.81 (t, J = 6.7 Hz, 1H), 2.76 (t, J = 6.7 Hz, 4H), 2.59 (t, J = 7.1Hz, 2H), 2.51 (q, J = 7.0 Hz, 2H), 2.11 (quint, J = 7.4 Hz, 1H), 2.05 (quint, J = 7.4 Hz, 1H), 1.10 (t, J = 7.1Hz, 3H), 0.98 (t, J = 7.1Hz, 3H). 13C-NMR (CDC13, 150 MHz) Mix of rotamers delta: 167.5, 166.5, 162.2 (d, JCF = 240 Hz), 161.4, 161.3, 156.8, 156.5, 144.1, 143.6, 139.8, 139.3, 136.8, 135.4, 131.5 (d, JCF = 3 Hz), 131.2 (d, JCF = 9 Hz), 131.1 (d, JCF = 3 Hz), 129.8 (m), 128.8, 128.0 (m), 127.7 (m), 127.4, 127.3, 127.2, 125.9 (m), 124.4 (m), 121.3, 121.2, 115.7 (d, JCF = 23 Hz), 115.6 (d, JCF = 23 Hz), 51.4, 50.4, 50.3, 50.1, 49.2, 47.8, 47.3, 46.1, 36.6, 36.5, 32.1, 32.0, 28.5, 28.4, 20.9, 20.8, 11.8;
Example 3(a) 1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5,6-trimethylenepyrimidin-4-one Intermediate B69 (87.1 g, 0.26 mol.) was suspended in dichloromethane (2.9 liter). 1-Hydroxybenzotriazole hydrate (35.2 g, 0.26 mol.) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (99.7 g, 0.52 mol.) were added and the suspension stirred for 45 minutes by which time complete solution had been obtained. Intermediate A30 (91.2 g, 0.26 mol.) was added as a solution in dichloromethane (100 ml) over 5 minutes and the solution stirred for 4 hours. Saturated ammonium chloride solution:water mixture (1:1, 1 liter) was added and the solution stirred for 10 minutes. The organic phase was separated and extracted with saturated ammonium chloride:water mixture (1:1, 1 liter), extracts were pH 6. The organic phase was separated and extracted with water (1 liter) containing acetic acid (10 ml), extract pH 5. The dichloromethane layer was separated and extracted with saturated sodium carbonate solution:water:saturated brine mixture (1:3:0.2, 1 liter), pH 10.5, then with saturated brine:water mixture (1:1, 1 liter). The brown solution was dried over anhydrous sodium sulfate in the presence of decolourising charcoal (35 g), filtered and the solvent removed in vacuo to give a dark brown foam. The foam was dissolved in iso-propyl acetate (100 ml) and the solvent removed in vacuo. The dark brown gummy residue was dissolved in boiling iso-propyl acetate (500 ml), cooled to room temperature, seeded and stirred overnight. The pale cream solid produced was filtered off and washed with iso-propyl acetate (100 ml). The solid was sucked dry in the sinter for 1 hour then recrystallized from iso-propyl acetate (400 ml). After stirring overnight the solid fowled was filtered off, washed with iso-propyl acetate (80 ml) and dried in vacuo to give the title compound, 110 g, 63.5% yield. 1H NMR (CDCl3, ca 1.9:1 rotamer mixture) delta 0.99 (6H, t), 2.10 (2H, m), 2.50 (4H, q), 2.58/2.62 (2H, 2*t), 2.70/2.82 (2H, 2*t), 2.86 (2H, t), 3.28/3.58 (2H, 2*t), 4.45/4.52 (2H, 2*s), 4.68/4.70 (2H, 2*s), 4.93 (2H, s), 6.95 (2H, m), 7.31 (2H, d), 7.31/7.37 (2H, 2*m), 7.48/7.52 (2H, d), 7.65 (2H, m), 7.72 (2H, m); MS (APCI) (M+H)+ 667; mp 125 C. (by DSC-assymetric endotherm).

  • 2
  • [ 304694-40-4 ]
  • [ 356058-42-9 ]
  • 1-(N-(2-(diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5,6-trimethylenepyrimidin-4-one hydrochloride [ No CAS ]
 

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