Home Cart 0 Sign in  

[ CAS No. 171482-05-6 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
Chemical Structure| 171482-05-6
Chemical Structure| 171482-05-6
Structure of 171482-05-6 * Storage: {[proInfo.prStorage]}
Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Quality Control of [ 171482-05-6 ]

Related Doc. of [ 171482-05-6 ]

Alternatived Products of [ 171482-05-6 ]

Product Details of [ 171482-05-6 ]

CAS No. :171482-05-6 MDL No. :MFCD13183776
Formula : C20H19ClF7NO2 Boiling Point : -
Linear Structure Formula :- InChI Key :DWCCMKXSGCKMJF-YNXGUESPSA-N
M.W : 473.81 Pubchem ID :10116311
Synonyms :

Calculated chemistry of [ 171482-05-6 ]

Physicochemical Properties

Num. heavy atoms : 31
Num. arom. heavy atoms : 12
Fraction Csp3 : 0.4
Num. rotatable bonds : 6
Num. H-bond acceptors : 10.0
Num. H-bond donors : 1.0
Molar Refractivity : 103.63
TPSA : 30.49 Ų

Pharmacokinetics

GI absorption : Low
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -5.26 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.0
Log Po/w (XLOGP3) : 5.53
Log Po/w (WLOGP) : 8.13
Log Po/w (MLOGP) : 4.77
Log Po/w (SILICOS-IT) : 5.83
Consensus Log Po/w : 4.85

Druglikeness

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

Water Solubility

Log S (ESOL) : -6.15
Solubility : 0.000334 mg/ml ; 0.000000705 mol/l
Class : Poorly soluble
Log S (Ali) : -5.93
Solubility : 0.000557 mg/ml ; 0.00000117 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -7.47
Solubility : 0.0000161 mg/ml ; 0.0000000339 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 4.2

Safety of [ 171482-05-6 ]

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 [ 171482-05-6 ]

* 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 [ 171482-05-6 ]

[ 171482-05-6 ] Synthesis Path-Downstream   1~19

  • 1
  • [ 252742-72-6 ]
  • [2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride [ No CAS ]
  • [ 170729-80-3 ]
  • 2
  • [ 171482-05-6 ]
  • [ 155742-64-6 ]
  • [ 219821-37-1 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In dimethyl sulfoxide; toluene at 15℃; for 2h;
With potassium carbonate In dimethyl sulfoxide; toluene at 15℃; 1 EXAMPLE 1 [2R- [2oc (R*), 3cc]]-5- [ [2- [1- [3, 5-bis (trifluoromethyl) phenyl] ethoxy]-3- (4- fluorophenyl)-4-morpholinyllmethyll-1, 2-dihydro-3H-1, 2, 4-triazol-3-one A mixture of the starting material as the hydrochloride salt of (2R, 2- alpha-R, 3a)-2- [l- [3, 5-bis (trifluoromethyl) phenyl] ethoxy-3- (4-fluorophenyl)-1, 4- oxazine (2a) (1.00 kg; 2.11 mol) and potassium carbonate (1.02 kg; 7.39 mol) in DMSO (2.2 L) and toluene (1.0 L) was cooled to 15°C. A slurry of amidrazone 3 (367 g; 2.22 mol) in toluene (1.5 L) was added. The mixture was stirred and then partitioned between toluene (4.0 L) and water (5.0 L). The phases were separated at 40°C. The organic layer (containing 4a) was washed with water (5.0 L) at 40°C and then partially concentrated at atmospheric pressure, providing intermediate 4a, which is used in the next step without isolation. The resulting solution containing intermediate 4a was heated to 140°C for 3 h and then allowed to cool to RT. The solids were filtered and dried in vacuo at 40 °C. The product (1.00 kg) was dissolved in methanol (10.0 L) and 50 g of Darco was added. The mixture was heated at 60°C for 1 h and then filtered at this temperature. The filtrates were allowed to cool slowly to RT. Water (5.0 L) was added slowly over 1 h. The slurry was cooled to 5 °C and the solids were filtered and dried in vacuo at 40 °C to yield 0.96 kg (85% overall yield) of the product [2R- [2oc (R*), 3cc]]-5- [ [2- [1- [3, 5-bis (trifluoromethyl) phenyl]- ethoxy]-3- (4-fluorophenyl)-4-morpholinyl] methyl]-1, 2-dihydro-3H-1, 2,4-triazol-3- one (i. e. 5- [ [2 (R)- [l (R)- [3, 5-bis (trifluoromethyl) phenyl]ethoxy]-3(S)-(4-fluorophenyl) -4-morpholinyl] methyl]-1, 2-dihydro-3H-1, 2, 4-triazol-3-one). Intermediate 4a: [a] D25=+84° (c=1.02, methanol) ;'H NMR (400 MHz, CDC13) 8 7. 64 (s, 2H), 7.34 (brt, J~7, 2H), 7.16 (s, 1H), 7.03 (t, J = 8. 4,2H), 5.8 (very br s, 2H), 4.88 (q, J = 6. 6,1H), 4.33 (d, J = 2. 8, 1H), 4.24 (td, J = 11. 6,2. 0, 1H), 3.77 (s, 2H), 3.66 (ddd, J= 11.6, 3.2, 1.6, 1H), 3.46 (d, J= 2.8, 1H), 3.31 (d, J = 14.5, 1H), 2.96 (brd, J= 11.6, 1H), 2.59 (d, J = 14.5, 1H), 2.50 (td, J = 12.1, 3.2, 1H), 1.47 (d, J = 6.6, 3H). Anal. Calc. for C24H2sF7N404 : C, 50.89 ; H, 4.45 ; F, 23.48 ; N, 9.89. Found: C, 50.48 ; H, 4.40 ; F, 23.43 ; N, 9.84. Final product la : Mp: 255 °C ; [α] = +69° (c=1.00, methanol) ;'H NMR (400 MHz, CD30D) 8 7.70 (s, 1H), 7.51 (m, 2H), 7.32 (s, 2H), 7.04 (t, J= 8.7, 2H), 4.94 (q, J= 6.3, 1H), 4.35 (d, J= 2.8, 1H), 4.28 (td, J = 11. 5,2. 8, 1H), 3.66 (ddd, J = 11. 5,3. 3,1. 6, 1H), 3.54 (d, J = 14. 3, 1H), 3.48 (d, J = 2.8, 1H), 2. 88 (br d, J = 11. 9,1H), 2.86 (d, J = 14.3, 1H), 2.49 (td, J = 11. 9,3. 6, 1H), 1.44 (d, J = 6.3, 3H) ;"C NMR (100 MHz, CD30D) 8 164.1 (d, J = 245.9), 158. 7,147. 6,147. 0,134. 1 (d, J= 3.1), 132.7 (d, J= 33.4), 132.4 (d, J= 8.0), 127.8 (m), 124.6 (q, J= 272.0), 122.3 (m), 116.1 (d, J = 21.6), 97.1, 73.7, 70.5, 60.4, 53.6, 52.2, 24.7. Anal. Calc. for C23H2lF7N403 : C, 51.69 ; H, 3.96 ; F, 24.88 ; N, 10.48. Found: C, 51.50 ; H, 3.82 ; F, 24.73 ; N, 10.44. HRMS : 534. 1480 (meas. ); 534.1502 (calc. for C23H21F7N4O3).
  • 3
  • [ 352-13-6 ]
  • [ 287930-75-0 ]
  • [ 171482-05-6 ]
YieldReaction ConditionsOperation in experiment
94.7% Stage #1: 4-flourophenylmagnesium bromide; (2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one In tetrahydrofuran; methanol at 15 - 20℃; for 0.916667h; Stage #2: With palladium 10% on activated carbon; ammonium formate; toluene-4-sulfonic acid In tetrahydrofuran; methanol Stage #3: With hydrogenchloride In di-isopropyl ether; water for 0.5h; Reflux; 2 Example II Preparation of Compounds of Formula III Was added to a 250ml 4-neck flask compound of formula II (13.4g, 30mmol), tetrahydrofuran (15ml), stirred and cooled to 15 , a solution of 4-fluorophenyl magnesium bromide (1.0MTHF solution, 40ml, 40mmol), dropwise Bi at room temperature with stirring 40min, the solution was dropwise added to ice-cooled methanol (30ml) and stirred for 15min, added p-toluenesulfonic acid (10.4g, 54.7mmol) in methanol (20ml) solution, 10% Pd / C (0.4g ) and ammonium formate (3.8g, 60mmol) until the reaction was complete. Filtered, washed methanol and concentrated to dryness. Add methyl isobutyl ketone (90ml), stirred, was added sodium carbonate (9.0g) / sodium citrate (10.8g) in water (120ml) was added. Liquid separation, the aqueous layer with methyl isobutyl ketone (40ml) and the combined organic layer, water (50ml) wash. Concentrated hydrochloric acid (5ml), filtered and the filtrate was evaporated to dryness at atmospheric pressure, adding isopropyl ether (50ml), refluxed for 30min. Cooling with stirring, ice-water bath was stirred 30min, filtered and washed with isopropyl ether, dried to give a white solid hydrochloride salt of the compound of formula III (13.4g, 94.7%).
86% Stage #1: 4-flourophenylmagnesium bromide; (2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one In tetrahydrofuran at 10 - 25℃; for 0.5h; Inert atmosphere; Stage #2: With palladium 10% on activated carbon; hydrogen; acetic acid In tetrahydrofuran; methanol at 20 - 25℃; for 2h; Stage #3: With hydrogenchloride at 20℃; for 0.5h; 1; 1-4 Example 1 Add 10.0g (2R)-4-benzyl-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]morpholine-3-one in a 250ml three-necked flask ketone And 20ml THF, stir until dissolved under nitrogen protection, cool to 10°C, add 4-fluorophenylmagnesium bromide tetrahydrofuran solution (1M, 35ml) dropwise, stir and react at 15°C - 25°C for 30min, After the reaction is completed (TLC monitoring, developing solvent: dichloromethane), the temperature is lowered to below 10°C, and then 30ml of frozen methanol is dropped into the reaction solution. Add acetic acid-methanol solution (2ml-20ml), add 10% Pd/C 3.00g, add hydrogen gas, keep the pressure at 20psi, and increase the temperature to 20 °C - 25 °C to react for 2h. After the reaction is complete (TLC monitoring, developing solvent: dichloromethane), suction filter, 10ml methanol rinse the filter cake, collect the filtrate and concentrate to dryness to obtain an off-white solid, and then add 100ml 4-methyl-2-pentanone, Then add aqueous solution of trisodium citrate dihydrate and NaHCO3 (8.50g, 7.50g, 120ml) and stir until it is clear, stand still and separate into layers, collect the organic phase, stir the organic phase at room temperature and add 3ml hydrochloric acid (37.0wt%) dropwise , Stir for 30min after dripping, After concentrating to dryness, add 20ml 4-methyl-2-pentanone, 4ml isopropanol and heat to 60°C and stir for 30min, then add 100ml n-heptane dropwise, and slowly cool to 0°C to crystallize for 2h. After filtering, 10 ml of n-heptane eluted the filter cake, and dried under reduced pressure at 75° C. to obtain 9.03 g of off-white solid, which is the key intermediate of Aprepitant, with a yield of 85.2%.
47.6 g With hydrogenchloride; hydrogen; toluene-4-sulfonic acid In tetrahydrofuran; methanol at 20 - 25℃; for 3h;
Stage #1: 4-flourophenylmagnesium bromide; (2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one With toluene-4-sulfonic acid In tetrahydrofuran; methanol at 0 - 10℃; Stage #2: In methanol at 20 - 30℃; for 4h; High pressure; 1 Synthesis of compound X 100 mL of tetrahydrofuran was added to 100.00 g (0.224) of Compound I, and the temperature was lowered to 0 ° C after stirring and dissolution. 300 mL of p-fluorophenyl magnesium bromide tetrahydrofuran solution (0.300mol) was added dropwise, and the solution was stirred for 30 minutes. After the reaction was completed, the temperature was controlled to 0-10 ° C, and the reaction solution was dropped into 150 mL of methanol to quench. A solution of sulfonic acid (0.368 mol) in methanol (70.05 g / 150 mL). After the addition is complete, pour the feed into a 1L hydrogenation reactor, maintain the hydrogenation pressure at 20 psi, control the temperature at 20-30 ° C, and hydrogenate for 4 h. After the reaction, the material was filtered, concentrated to dryness in vacuo, 500 mL of methyl isobutyl ketone and 100 mL of a sodium citrate and sodium bicarbonate buffer solution were added, and the mixture was stirred and separated. The organic phase was sequentially purified water and saturated brine. Wash and separate liquid. Add 7.5mL of concentrated hydrochloric acid to the organic phase, stir to reflux, evaporate a small amount of solvent, and precipitate a large amount of solids in the system. Cool to 20 ° C, crystallize for 3h, filter, rinse, and dry to obtain 76.6g of off-white. Solid compound X, yield: 72.33%.

  • 4
  • [ 171482-05-6 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
84% Stage #1: [2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride With sodium hydrogencarbonate In ethyl acetate Stage #2: With N-chloro-succinimide; potassium carbonate; 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide; toluene at 20℃; for 5h; Further stages.;
  • 5
  • [ 30071-93-3 ]
  • [ 171482-05-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 97 percent / borane-methyl sulfide complex; (S)-Me-CBS / various solvent(s); toluene / 1 h / -5 °C 2: 3.51 kg / BF3*Et2O / acetonitrile / 2 h / 20 °C 3: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
Multi-step reaction with 3 steps 1: 97 percent / borane-methyl sulfide complex; (S)-Me-CBS / various solvent(s); toluene / 1 h / -5 °C 2: boron trifluoride etherate / toluene; heptane / 1 h / 20 °C 3: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
Multi-step reaction with 4 steps 1: 97 percent / borane-methyl sulfide complex; (S)-Me-CBS / various solvent(s); toluene / 1 h / -5 °C 2: boron trifluoride etherate / toluene; heptane / 1 h / 20 °C 3: KO-t-Bu / 2-methyl-propan-2-ol; hexane / 16 h / 22 °C 4: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
  • 6
  • [ 127852-28-2 ]
  • [ 171482-05-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 3.51 kg / BF3*Et2O / acetonitrile / 2 h / 20 °C 2: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
Multi-step reaction with 2 steps 1: boron trifluoride etherate / toluene; heptane / 1 h / 20 °C 2: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
Multi-step reaction with 3 steps 1: boron trifluoride etherate / toluene; heptane / 1 h / 20 °C 2: KO-t-Bu / 2-methyl-propan-2-ol; hexane / 16 h / 22 °C 3: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
  • 7
  • [ 110843-90-8 ]
  • [ 171482-05-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: 80 percent / lithium tri(sec-butyl)borohydride; sodium hydroxide; hydrogen peroxide / tetrahydrofuran; H2O / 1 h / 10 °C 2: acetonitrile / 5 - 34 °C 3: 3.51 kg / BF3*Et2O / acetonitrile / 2 h / 20 °C 4: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
Multi-step reaction with 4 steps 1: 80 percent / lithium tri(sec-butyl)borohydride; sodium hydroxide; hydrogen peroxide / tetrahydrofuran; H2O / 1 h / 10 °C 2: 91 percent / DBU / toluene; heptane / 18 h / 20 °C 3: boron trifluoride etherate / toluene; heptane / 1 h / 20 °C 4: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
Multi-step reaction with 5 steps 1: 80 percent / lithium tri(sec-butyl)borohydride; sodium hydroxide; hydrogen peroxide / tetrahydrofuran; H2O / 1 h / 10 °C 2: 91 percent / DBU / toluene; heptane / 18 h / 20 °C 3: boron trifluoride etherate / toluene; heptane / 1 h / 20 °C 4: KO-t-Bu / 2-methyl-propan-2-ol; hexane / 16 h / 22 °C 5: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
  • 8
  • [ 104-63-2 ]
  • [ 171482-05-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: 76 percent / tetrahydrofuran; H2O / 21 h / Heating 2: acetonitrile / 5 - 34 °C 3: 3.51 kg / BF3*Et2O / acetonitrile / 2 h / 20 °C 4: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
Multi-step reaction with 4 steps 1: 76 percent / tetrahydrofuran; H2O / 21 h / Heating 2: 91 percent / DBU / toluene; heptane / 18 h / 20 °C 3: boron trifluoride etherate / toluene; heptane / 1 h / 20 °C 4: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
Multi-step reaction with 5 steps 1: 76 percent / tetrahydrofuran; H2O / 21 h / Heating 2: 91 percent / DBU / toluene; heptane / 18 h / 20 °C 3: boron trifluoride etherate / toluene; heptane / 1 h / 20 °C 4: KO-t-Bu / 2-methyl-propan-2-ol; hexane / 16 h / 22 °C 5: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
Multi-step reaction with 4 steps 1: acetonitrile / 5 - 34 °C 2: 3.51 kg / BF3*Et2O / acetonitrile / 2 h / 20 °C 3: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
Multi-step reaction with 4 steps 1: 91 percent / DBU / toluene; heptane / 18 h / 20 °C 2: boron trifluoride etherate / toluene; heptane / 1 h / 20 °C 3: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
Multi-step reaction with 5 steps 1: 91 percent / DBU / toluene; heptane / 18 h / 20 °C 2: boron trifluoride etherate / toluene; heptane / 1 h / 20 °C 3: KO-t-Bu / 2-methyl-propan-2-ol; hexane / 16 h / 22 °C 4: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
Multi-step reaction with 5 steps 1: 68 percent / ethanol; hexane / 20 °C 2: 80 percent / lithium tri(sec-butyl)borohydride; sodium hydroxide; hydrogen peroxide / tetrahydrofuran; H2O / 1 h / 10 °C 3: acetonitrile / 5 - 34 °C 4: 3.51 kg / BF3*Et2O / acetonitrile / 2 h / 20 °C 5: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
Multi-step reaction with 5 steps 1: 68 percent / ethanol; hexane / 20 °C 2: 80 percent / lithium tri(sec-butyl)borohydride; sodium hydroxide; hydrogen peroxide / tetrahydrofuran; H2O / 1 h / 10 °C 3: 91 percent / DBU / toluene; heptane / 18 h / 20 °C 4: boron trifluoride etherate / toluene; heptane / 1 h / 20 °C 5: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
Multi-step reaction with 6 steps 1: 68 percent / ethanol; hexane / 20 °C 2: 80 percent / lithium tri(sec-butyl)borohydride; sodium hydroxide; hydrogen peroxide / tetrahydrofuran; H2O / 1 h / 10 °C 3: 91 percent / DBU / toluene; heptane / 18 h / 20 °C 4: boron trifluoride etherate / toluene; heptane / 1 h / 20 °C 5: KO-t-Bu / 2-methyl-propan-2-ol; hexane / 16 h / 22 °C 6: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
Multi-step reaction with 3 steps 1.1: tetrahydrofuran / Reflux 2.1: trifluoroacetic anhydride / acetonitrile / 1 h / 5 - 30 °C 2.2: 3 h 3.1: tetrahydrofuran; methanol / 0.92 h / 15 - 20 °C 3.3: 0.5 h / Reflux

Reference: [1]Brands, Karel M. J.; Payack, Joseph F.; Rosen, Jonathan D.; Nelson, Todd D.; Candelario, Alexander; Huffman, Mark A.; Zhao, Matthew M.; Li, Jing; Craig, Bridgette; Song, Zhiguo J.; Tschaen, David M.; Hansen, Karl; Devine, Paul N.; Pye, Philip J.; Rossen, Kai; Dormer, Peter G.; Reamer, Robert A.; Welch, Christopher J.; Mathre, David J.; Tsou, Nancy N.; McNamara, James M.; Reider, Paul J. [Journal of the American Chemical Society, 2003, vol. 125, # 8, p. 2129 - 2135]
[2]Brands, Karel M. J.; Payack, Joseph F.; Rosen, Jonathan D.; Nelson, Todd D.; Candelario, Alexander; Huffman, Mark A.; Zhao, Matthew M.; Li, Jing; Craig, Bridgette; Song, Zhiguo J.; Tschaen, David M.; Hansen, Karl; Devine, Paul N.; Pye, Philip J.; Rossen, Kai; Dormer, Peter G.; Reamer, Robert A.; Welch, Christopher J.; Mathre, David J.; Tsou, Nancy N.; McNamara, James M.; Reider, Paul J. [Journal of the American Chemical Society, 2003, vol. 125, # 8, p. 2129 - 2135]
[3]Brands, Karel M. J.; Payack, Joseph F.; Rosen, Jonathan D.; Nelson, Todd D.; Candelario, Alexander; Huffman, Mark A.; Zhao, Matthew M.; Li, Jing; Craig, Bridgette; Song, Zhiguo J.; Tschaen, David M.; Hansen, Karl; Devine, Paul N.; Pye, Philip J.; Rossen, Kai; Dormer, Peter G.; Reamer, Robert A.; Welch, Christopher J.; Mathre, David J.; Tsou, Nancy N.; McNamara, James M.; Reider, Paul J. [Journal of the American Chemical Society, 2003, vol. 125, # 8, p. 2129 - 2135]
[4]Brands, Karel M. J.; Payack, Joseph F.; Rosen, Jonathan D.; Nelson, Todd D.; Candelario, Alexander; Huffman, Mark A.; Zhao, Matthew M.; Li, Jing; Craig, Bridgette; Song, Zhiguo J.; Tschaen, David M.; Hansen, Karl; Devine, Paul N.; Pye, Philip J.; Rossen, Kai; Dormer, Peter G.; Reamer, Robert A.; Welch, Christopher J.; Mathre, David J.; Tsou, Nancy N.; McNamara, James M.; Reider, Paul J. [Journal of the American Chemical Society, 2003, vol. 125, # 8, p. 2129 - 2135]
[5]Brands, Karel M. J.; Payack, Joseph F.; Rosen, Jonathan D.; Nelson, Todd D.; Candelario, Alexander; Huffman, Mark A.; Zhao, Matthew M.; Li, Jing; Craig, Bridgette; Song, Zhiguo J.; Tschaen, David M.; Hansen, Karl; Devine, Paul N.; Pye, Philip J.; Rossen, Kai; Dormer, Peter G.; Reamer, Robert A.; Welch, Christopher J.; Mathre, David J.; Tsou, Nancy N.; McNamara, James M.; Reider, Paul J. [Journal of the American Chemical Society, 2003, vol. 125, # 8, p. 2129 - 2135]
[6]Brands, Karel M. J.; Payack, Joseph F.; Rosen, Jonathan D.; Nelson, Todd D.; Candelario, Alexander; Huffman, Mark A.; Zhao, Matthew M.; Li, Jing; Craig, Bridgette; Song, Zhiguo J.; Tschaen, David M.; Hansen, Karl; Devine, Paul N.; Pye, Philip J.; Rossen, Kai; Dormer, Peter G.; Reamer, Robert A.; Welch, Christopher J.; Mathre, David J.; Tsou, Nancy N.; McNamara, James M.; Reider, Paul J. [Journal of the American Chemical Society, 2003, vol. 125, # 8, p. 2129 - 2135]
[7]Brands, Karel M. J.; Payack, Joseph F.; Rosen, Jonathan D.; Nelson, Todd D.; Candelario, Alexander; Huffman, Mark A.; Zhao, Matthew M.; Li, Jing; Craig, Bridgette; Song, Zhiguo J.; Tschaen, David M.; Hansen, Karl; Devine, Paul N.; Pye, Philip J.; Rossen, Kai; Dormer, Peter G.; Reamer, Robert A.; Welch, Christopher J.; Mathre, David J.; Tsou, Nancy N.; McNamara, James M.; Reider, Paul J. [Journal of the American Chemical Society, 2003, vol. 125, # 8, p. 2129 - 2135]
[8]Brands, Karel M. J.; Payack, Joseph F.; Rosen, Jonathan D.; Nelson, Todd D.; Candelario, Alexander; Huffman, Mark A.; Zhao, Matthew M.; Li, Jing; Craig, Bridgette; Song, Zhiguo J.; Tschaen, David M.; Hansen, Karl; Devine, Paul N.; Pye, Philip J.; Rossen, Kai; Dormer, Peter G.; Reamer, Robert A.; Welch, Christopher J.; Mathre, David J.; Tsou, Nancy N.; McNamara, James M.; Reider, Paul J. [Journal of the American Chemical Society, 2003, vol. 125, # 8, p. 2129 - 2135]
[9]Brands, Karel M. J.; Payack, Joseph F.; Rosen, Jonathan D.; Nelson, Todd D.; Candelario, Alexander; Huffman, Mark A.; Zhao, Matthew M.; Li, Jing; Craig, Bridgette; Song, Zhiguo J.; Tschaen, David M.; Hansen, Karl; Devine, Paul N.; Pye, Philip J.; Rossen, Kai; Dormer, Peter G.; Reamer, Robert A.; Welch, Christopher J.; Mathre, David J.; Tsou, Nancy N.; McNamara, James M.; Reider, Paul J. [Journal of the American Chemical Society, 2003, vol. 125, # 8, p. 2129 - 2135]
[10]Current Patent Assignee: HANSOH PHARMACEUTICAL GROUP CO LTD - CN103030668, 2016, B
  • 9
  • [2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride [ No CAS ]
  • [ 170729-80-3 ]
  • 10
  • [ 287930-73-8 ]
  • [ 171482-05-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: acetonitrile / 5 - 34 °C 2: 3.51 kg / BF3*Et2O / acetonitrile / 2 h / 20 °C 3: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
Multi-step reaction with 3 steps 1: 91 percent / DBU / toluene; heptane / 18 h / 20 °C 2: boron trifluoride etherate / toluene; heptane / 1 h / 20 °C 3: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
Multi-step reaction with 4 steps 1: 91 percent / DBU / toluene; heptane / 18 h / 20 °C 2: boron trifluoride etherate / toluene; heptane / 1 h / 20 °C 3: KO-t-Bu / 2-methyl-propan-2-ol; hexane / 16 h / 22 °C 4: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
Multi-step reaction with 2 steps 1.1: trifluoroacetic anhydride / acetonitrile / 1 h / 5 - 30 °C 1.2: 3 h 2.1: tetrahydrofuran; methanol / 0.92 h / 15 - 20 °C 2.3: 0.5 h / Reflux

Reference: [1]Brands, Karel M. J.; Payack, Joseph F.; Rosen, Jonathan D.; Nelson, Todd D.; Candelario, Alexander; Huffman, Mark A.; Zhao, Matthew M.; Li, Jing; Craig, Bridgette; Song, Zhiguo J.; Tschaen, David M.; Hansen, Karl; Devine, Paul N.; Pye, Philip J.; Rossen, Kai; Dormer, Peter G.; Reamer, Robert A.; Welch, Christopher J.; Mathre, David J.; Tsou, Nancy N.; McNamara, James M.; Reider, Paul J. [Journal of the American Chemical Society, 2003, vol. 125, # 8, p. 2129 - 2135]
[2]Brands, Karel M. J.; Payack, Joseph F.; Rosen, Jonathan D.; Nelson, Todd D.; Candelario, Alexander; Huffman, Mark A.; Zhao, Matthew M.; Li, Jing; Craig, Bridgette; Song, Zhiguo J.; Tschaen, David M.; Hansen, Karl; Devine, Paul N.; Pye, Philip J.; Rossen, Kai; Dormer, Peter G.; Reamer, Robert A.; Welch, Christopher J.; Mathre, David J.; Tsou, Nancy N.; McNamara, James M.; Reider, Paul J. [Journal of the American Chemical Society, 2003, vol. 125, # 8, p. 2129 - 2135]
[3]Brands, Karel M. J.; Payack, Joseph F.; Rosen, Jonathan D.; Nelson, Todd D.; Candelario, Alexander; Huffman, Mark A.; Zhao, Matthew M.; Li, Jing; Craig, Bridgette; Song, Zhiguo J.; Tschaen, David M.; Hansen, Karl; Devine, Paul N.; Pye, Philip J.; Rossen, Kai; Dormer, Peter G.; Reamer, Robert A.; Welch, Christopher J.; Mathre, David J.; Tsou, Nancy N.; McNamara, James M.; Reider, Paul J. [Journal of the American Chemical Society, 2003, vol. 125, # 8, p. 2129 - 2135]
[4]Current Patent Assignee: HANSOH PHARMACEUTICAL GROUP CO LTD - CN103030668, 2016, B
  • 12
  • [ 502536-97-2 ]
  • [ 171482-05-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: boron trifluoride etherate / toluene; heptane / 1 h / 20 °C 2: KO-t-Bu / 2-methyl-propan-2-ol; hexane / 16 h / 22 °C 3: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
Multi-step reaction with 2 steps 1: boron trifluoride etherate / toluene; heptane / 1 h / 20 °C 2: 47.6 g / 4-toluenesulfonic acid; H2; HCl / Pd/C / tetrahydrofuran; methanol / 3 h / 20 - 25 °C / 1034.32 Torr
  • 13
  • [ 155764-79-7 ]
  • [ 171482-05-6 ]
  • [ 1349902-81-3 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In N,N-dimethyl-formamide at 10 - 20℃; Large scale; 1 EXAMPLE 1 [0027] [0028] A mixture of starting materials (2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride 2 (2 kg; 4.23 mol) and potassium carbonate (1.75 kg; 12.7 mol) was cooled to about 10° C. in the solvent N,N-dimethyl formamide (DMF). A slurry of amidrazone 3a (962 g; 4.65 mol) dissolved in DMF (4 L) was added. The reaction mixture was stirred at room temperature. The mixture was extracted with ethyl acetate (6 L) and water (8 L) and then phases weere separated after the reaction was completed, the layer of ethyl acetate was washed with saturated aqueous solution of NaCl (8 L×3) and combined, the majority of organic solvent ethyl acetate (about 20 L) was recovered under normal pressure, to obtain intermediate 4a. The intermediate 4a was directly put into the next step of reaction without separation. A water-ethanol mixed solvent and about 400 g potassium hydroxide was added into a reaction bottle, the reaction solution was reacted for about 1 hour at about 90-100° C., the majority of organic solvent ethanol was recovered under normal pressure after the reaction was completed. The reaction solution was cooled to room temperature, and a large amount of solid precipitated. Purifying steps: the above-mentioned solid was filtrated, and dried in vacuum at 40° C. The resultant product was dissolved in methanol (10 L), decolorized by adding appropriate amount of activated carbon, the mixture was heated and refluxed for 1 hour at about 60° C., and filtrated at the same temperature. The filtrate was cooled to room temperature, and a large amount of water was added slowly to the filtrate. The slurry was cooled to about 5° C. Solid was filtrated and dried in vacuum at 40° C., to obtain the product aprepitant (1940 g, 86%). [0029] Spectroscopic date of the intermediate 4a: [0030] 1HNMR (600 MHz, CDCl3): δ 7.64 (s, 1H), 7.35 (brs, 2H), 7.16 (s, 2H), 7.03 (t, J=8.4 Hz, 2H), 5.47 (s, 1H), 4.88 (dd, J=12.8, 6.6 Hz, 1H), 4.34 (d, J=2.22 Hz, 1H), 4.23 (t, J=11.6 Hz, 1H), 3.64 (d, J=10.7 Hz, 1H), 3.43 (s, 1H), 3.27 (d, J=14.3 Hz, 1H), 2.95 (d, J=12.1 Hz, 1H), 253-2.44 (m, 2H), 1.45 (s, 9H). 13CNMR (150 MHz, CDCl3): δ 163.5, 161.8, 154.9, 145.4, 132.4, 132.0, 131.7, 131.5, 131.3, 130.7, 130.6, 126.2, 123.9, 122.1, 121.4, 115.4, 115.2, 95.4, 72,3, 68.8, 59.4, 56.4, 52.4, 28.3, 24.4, MS (EI) m/z: 608.81 (M+1). [0031] Spectroscopic data of aprepitant: [0032] 1H NMR (CD3OD, 600 MHz): δ 7.69 (s, 1H), 7.41 (br, s, 2H), 7.22 (s, 2H), 6.95 (t, J=8.7 Hz, 2H), 4.85 (q, J=6.6 Hz, 1H), 4.27 (d, J=2.9 Hz, 1H), 4.19 (dt, J=2.3, 11.6 Hz, 1H) 3.57 (d, J=6.6 Hz, 1H), 3.44 (d, J=14.3 Hz, 1H), 2.78 (m, 2H), 2.40 (dt, J=3.5, 11.8 Hz, 1H), 1.35 (d, J=6.6 Hz, 3H), 13C NMR (CD3OD, 150 MHz): δ 163.4, 161.8, 157.2, 146.1, 145.5, 132.7, 131.6, 131.4, 131.0, 130.9, 126.4, 124.1, 122.3, 120.8, 114.7, 114.6, 95.7, 72.3, 69.0, 59.0, 52.2, 50.8, 23.2. HR-ESI-MS: 557.1389, (C23H21F7N4NaO3 cal. 557.1399).
  • 14
  • [ 909784-69-6 ]
  • [ 171482-05-6 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In N,N-dimethyl-formamide at 10 - 20℃; 7 EXAMPLE 7 EXAMPLE 7 A mixture of starting materials (2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride 2 (5 g; 10.5 mmol) and potassium carbonate (2.7 g; 20 mmol) was cooled to about 10° C., in the solvent DMF. A slurry of amidrazone 3b (2.07 g; 11.6 mol) dissolved in DMF was added. The reaction mixture was stirred at room temperature. The mixture was extracted with ethyl acetate and water and phases were separated after the reaction was completed. The layer of ethyl acetate was washed with saturated aqueous solution of NaCl and combined. Ethyl acetate was concentrated under reduced pressure to obtain oil substance 4b, which was dissolved in a mixed solution of ethanol and water (1:1), and 2 g of solid potassium hydroxide was added. The reaction was performed at 90-100° C. for about 2 hours. The majority of ethanol was removed by concentrating under reduced pressure. The solution left was poured into a large amount of ice water, and a large amount of solid precipitated, which was then purified according to the method of Example 1 to obtain aprepitant (2.92 g, yield 52%).
  • 15
  • [ 171482-05-6 ]
  • [ 155742-64-6 ]
  • [ 219821-37-1 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In N,N-dimethyl-formamide at 10 - 20℃; 8 EXAMPLE 8 EXAMPLE 8 A mixture of starting materials (2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride 2 (5 g; 10.5 mmol) and potassium carbonate (2.7 g; 20 mmol) was cooled to about 10° C. in tha solvent DMF. A slurry of amidrazone 3c (1.91 g; 11.6 mol) dissolved in DMF was added. The reaction mixture was stirred at room temperature. The mixture was extracted with ethyl acetate and water and phases were separated after the reaction was completed. The layer of ethyl acetate was washed with saturated aqueous solution of NaCl and combined. Ethyl acetate was concentrated under reduced pressure to obtain oily substance 4c, which was dissolved in a mixed solution of ethanol and water (1:1) and 2 g of solid potassium hydroxide was added. The reaction was performed at 90-100° C. for about 2 hours. The majority of ethanol was removed by concentrating under reduced pressure. The solution left was poured into a large amount of ice water, and a large amount of solid precipitated, which was then purified according to the method of Example 1 to obtain aprepitant (336 g, yield 60%).
Stage #1: [2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride With potassium hydroxide In N,N-dimethyl-formamide for 0.5h; Stage #2: N'-(1-amino-2-chloroethylidene)hydrazine carboxylic acid methyl ester In N,N-dimethyl-formamide for 4.16h; 1 Potash (5. 10g, 36.90 mmol, 1.75 equiv.) was added to a suspension of the hydrochloride 11 ( 10 g, 21 . 10 mmol) in DMF (20 ml) at the laboratory temperature and the suspension was stirred for 30 mins and then addition of a suspension of amidrazone (3.83 g, 23.19 mmol, 1 .1 equiv.) in DMF (10 mL) was started within ca. 10 min. Stirring at the laboratory temperature followed for 4 h. The reaction was monitored with HPLC. The reaction mixture was then diluted with MIBK ( 100 ml) and water ( 100 ml) and brine (20 ml) were added under intensive stirring; the phases were thoroughly mixed and then separated. The aqueous phase was still washed with MIBK (50 ml). The combined organic phase was washed with water (50 ml) and brine (20 ml). The solution of the intermediate obtained this way was heated up to boil and the residual water was removed by azeotropic distillation. Reflux for 17 h, the mixture was concentrated by distillation, ca. 85 mL of MIBK removed. The solution was slowly cooled to the laboratory temperature while being stirred and then cooled to 5 °C; crystals were removed by filtration and washed with cold MIBK (3 x 10 ml) and air-dried. 8. 15 g (72%) of crystals were obtained, purity 99.80 %, polymorph form I.
With N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate In 5,5-dimethyl-1,3-cyclohexadiene; dimethyl sulfoxide at 20 - 25℃; Inert atmosphere; wherein the specific process of step (1) is:1) The 100L reaction vessel with nitrogen, dimethyl sulfoxide, (2R, 3S) -2 - [(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy (3-fluorophenyl) morpholine hydrochloride and xylene, stirred and dissolved, potassium carbonate was added, stirred at20-25 ° C, and then (AR-3) 2- (2-chloro-1- Iminoethyl) hydrazinecarboxylate, benzyltriethylammonium chloride for 18-22h;2) After step 1) After the reaction was completed, xylene and water were added to the reaction system, and the mixture wasallowed to standat 37-43 ° C for 30 minutes. The mixturewas collected and separated. After the addition of saturated brine, the organic layer was added at 32-38 ° C After stirring for 5 min, the separatedlayers were collected and the organic phases were separated. The combined aqueous phase was transferred into a kettle. The xylene was added at 32-38 ° C for 5 min. Theaqueous phase was separated and the organic phase was combined. dried over anhydrous magnesium sulfate was stirred for 30min, the drying agent was removed by filtration, leaching using xylenewash, to give a pale yellow filtrate to give 2R- [1R- [3,5- bis (trifluoromethyl) phenyl] ethoxy] - 3S- (4-fluorophenyl) -4-(N-methoxycarbonyl-2-aminoethhydrazono) -morpholine in xylene.
With potassium carbonate In 5,5-dimethyl-1,3-cyclohexadiene; dimethyl sulfoxide at 0 - 10℃; for 16h; 1 Example 1 The reaction bottle (II) compound is added (100.0 g), anhydrous potassium carbonate (102.0 g), dimethyl sulfoxide (200 ml), xylene (200 ml), 0 - 10 °C stirring for 10 - 15 minutes, adding the compound (III) (39.0 g), stirring for about 16 hours, plus xylene and water, stirring 10 minutes, layered, the organic layer is washed with water, dried with anhydrous sodium sulfate, filtered, washing the filter cake for xylene, filtrate 130 °C -139 °C reaction 4 hours. Stirring cooling to 0 °C -10 °C, filtering, the filter cake is xylene washing. Solid vacuum drying 20 hours, to obtain compound (I) 109.0 g, molar yield 97.7%. HPLC: 99.97%, total isomer 0.017%.

  • 16
  • [ 460-00-4 ]
  • [ 287930-75-0 ]
  • [ 171482-05-6 ]
YieldReaction ConditionsOperation in experiment
93.1% Stage #1: 1-Bromo-4-fluorobenzene; (2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]]ethoxy-morpholin-3-one With palladium on activated charcoal; hydrogen; magnesium In tetrahydrofuran Stage #2: With hydrogenchloride In tetrahydrofuran; water 1 4-Benzyl-2-hydroxy-morpholin-3-oneII25g,Trifluoroacetic anhydride 50 gAnd anhydrous acetonitrile 80 gAdded to the reactor,The mixture was stirred at 5 ° C for 1 hour,Join(R) -1- [3,5-bis (trifluoromethyl) phenyl] ethanol III60g andBoron trifluoride etherate17g,The condensation reaction was stirred at 25 ° C for 4 hours,The reaction solution was treated and crystallized to give compound IV. To the reaction vessel was added magnesium 2 g,Tetrahydrofuran 40 g and p-fluorobromobenzene 16 g,The heating initiates a reaction to disappearance of magnesium,That is, the format reagent and cooling stand-by;Compound IV was dissolved in 100 g of tetrahydrofuran as a solution,The above format reagent was added dropwise until the reaction was complete,The reaction was quenched by the addition of 16 g of methanol,0.5 g of palladium on carbon was added to the reaction solution,Hydrogenation was carried out until hydrogenation was carried out until the reaction was complete,After filtration, the filtrate was evaporated to give compound . 33 g of methyl isobutyl ketone was added,3 g of sodium bicarbonate and 5 g of sodium citrate,Stirring and separating the organic layer,Organic layer by adding 37% hydrochloric acid 6g hydrochloric acidification reaction,The reaction solution was pumped into an autoclave to crystallize, centrifuged, dried,To obtain 53.1 g of the powdery product of the target product Compound I,The total yield was 93.1% (based on 4-benzyl-2-hydroxy-morpholin-3-one II) and the HPLC purity was 99.0% or more.
  • 17
  • [ 2101193-67-1 ]
  • [ 171482-05-6 ]
  • [ 265121-01-5 ]
YieldReaction ConditionsOperation in experiment
89.5% With potassium carbonate In methanol at 0℃; for 2h; 1-4 35.84 g of the product obtained, 42.64 g (90 mmol) of [2R-2a (R), 3a]-2-[1-[3, 5-bis (trifluoromethyl), phenyl]ethoxy]-3-(4-fluorophenyl)-3-morpholine hydrochloride and 100 ml of methanol were added to the reaction flask and stirred to dissolve. The reaction temperature was controlled to 0 ° C, 13.8 g (100 mmol) of potassium carbonate was added, and the mixture was stirred for 2 h, filtered, and the filtrate was concentrated to dry. 240 ml of ethyl acetate and 240 ml of water was added, stirred for 30 min, dispense, the organic layer was collected, dried over anhydrous sodium sulfate, filtered and evaporated to dryness, it was recrystallized from ethyl acetate and dried in vacuo to give white crystals, the yield was 89.5% and the purity was 98.87%.
  • 18
  • C3H4BrN3O [ No CAS ]
  • [2R-[2α(R*),3α]]-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride [ No CAS ]
  • [ 170729-80-3 ]
YieldReaction ConditionsOperation in experiment
97.9% With diethyl sulfate; triethylamine; lithium diisopropyl amide; In dimethylsulfoxide-d6; 5,5-dimethyl-1,3-cyclohexadiene; at 33℃; for 14h;Inert atmosphere; This embodiment provides a preparation process of aprepitant, comprising the following steps:Setp1, firstly add compound A and compound B to a mixed solvent of N,N-dimethylformamide and triethylamine.Mixing and dissolving to obtain a mixed solution; wherein, the mass ratio of the compound A to the compound B is 1.6; the mass ratio of the mixed solvent of N,N-dimethylformamide and triethylamine in the mixed solvent is 1:0.3, the mixed solution The solute mass fraction was 34%.Setp2, under a nitrogen atmosphere,Adding diisopropylamine lithium to the mixed solution for uniform mixing;The addition mass of lithium diisopropylamide is 1/3 of the sum of the masses of the compound A and the compound B.Setp3, nitrogen gas protection, stirring, adding a solution of diethyl sulfate in xylene; diethyl sulfate is added in a mass of 0.07% of the sum of the mass of compound A and compound B, and a solution of diethyl sulfate in xylene The mass percent concentration was 76%, and the drop rate of the solution of diethyl sulfate in xylene was 28 ml/min.Setp4, after the end of the dropwise addition, under nitrogen protection, the reaction was stirred at 33 C for 14 h;Setp5, the reaction product of the Setp4 is separated and purified to obtain the final product of aprepitant; the specific steps of separation and purification include:Setp51, extraction and recovery: Add the reaction solution produced by Setp4 to n-butanol, dichloromethane and water, the mass ratio of n-butanol to methylene chloride is 1:3; stir at 35 C for 60 min, then add saturation The organic layer obtained by the layering treatment of the brine is dried and dried by anhydrous magnesium sulfate;Setp52, dissolving: dissolving the crude aprepitant in an acetone solvent;Setp53, reflux decolorization: adding 1% diatomaceous earth of the crude quality of aprepitant, vacuum distillation, reflux decolorization for 20 min;Setp54, crystallization: the decolorizing solution is added to the acetone washing, and then the decolorizing solution recovered after the filtration treatment is subjected to crystallization treatment; the specific operation of the crystallization is as follows: first, the filtered decolorizing solution is heated to 55 C; secondly, under stirring, Water at a temperature of 20 C was added dropwise at a rate of 16 ml/min, and the stirring speed was 50 r/min. Finally, after the completion of the dropwise addition, the solution was cooled to 0 to 5 C for crystallization for 0.6 h.Setp55, filtration, washing: the crystallization liquid is filtered, and the mixture is washed with acetone and water at a mass ratio of 1:0.6, and the filter cake is washed to obtain aprepitant wet product;Setp56, drying: vacuum drying of aprepitant wet product to obtain aprepitant dry product, vacuum degree 0.05Mpa, drying temperature 40 C, drying time 12h, turning once every hour; finally crushed , screening, packaging to obtain finished products.Wherein the reaction of the compound A and the compound B is as shown in the formula (1):The yield of the final product obtained from aprepitant was 97.9%, the purity (HPLC) was 99.9%, and the maximum single impurity content was0.02%.
  • 19
  • [ CAS Unavailable ]
  • [ 352-13-6 ]
  • [ 171482-05-6 ]
YieldReaction ConditionsOperation in experiment
42.5 g Stage #1: (R)-4-benzyl-2-((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)morpholine; 4-flourophenylmagnesium bromide In tetrahydrofuran at 10 - 25℃; for 0.5h; Inert atmosphere; Stage #2: With hydrogenchloride; toluene-4-sulfonic acid In methanol; water at 0 - 10℃; Inert atmosphere; Further stages; 1 Step 1: Preparation of (2R, 3S)-2-((R)-1- (3,5-bis(trifluoromethyl)phenyl-) ethoxy) -3-(4-fluorobenzene)morpholine hydrochloride: A high-purity aprepitant preparation method, the specific steps are as follows:Step 1: Preparation of (2R, 3S) -2-((R) -1- (3,5-bis (trifluoromethyl) phenyl) ethoxy) -3- (4-fluorobenzene) morpholine salt Acid salt: Add the measured (R) -4-benzyl-2-((R) -1- (3,5-bis (trifluoromethyl) phenyl) ethoxy) in a 1000mL three-necked bottle in sequence Morphorin-3-one 50g and tetrahydrofuran (100mL, stirred under nitrogen replacement protection until dissolved, temperature controlled at 10 , using a 250mL dropping funnel to drop 163.69mL 4-fluorophenyl magnesium bromide into the above solution, After about 1h, the solution was gray-black. The cold bath was removed. The temperature was raised to 20-25 ° C and the reaction was kept for 30 minutes. After the reaction was completed, the internal temperature was kept below 5 ° C for standby, and the temperature was controlled below 5 ° C. Add it to a 2000mL three-necked bottle containing 150mL of cooled methanol and lower the temperature to below 0 . Within 10 , quickly add 100mL of methanol containing 44.8g of p-toluenesulfonic acid monohydrate to the above turbid solution. Become a clear liquid, then replace with nitrogen twice, add 15g of palladium-carbon catalyst with 5% wet mass fraction, after replacing with hydrogen three times, the pressure is 0.015MPa, rise to 20 ~ 25 , stir vigorously for 1 hour, suction filter, use Methanol 100mL The filtrate was concentrated at 40 ° C under reduced pressure to obtain an off-white solid. To the above white solid was added 4-methyl-2-pentanone 350mL and stirred, and then 42.5g of trisodium citrate dihydrate and 37.5g containing sodium bicarbonate were added Stir 600mL of the aqueous solution until it is clear, separate the layers at rest, separate the upper organic phase, discard the lower aqueous phase, add 15g of activated carbon to the organic layer, decolorize at 30-45 ° C for 20-30 minutes, hot filter, use 50mL of hot methyl iso The filter cake was washed with butyl ketone, and the organic phases were combined. The filtrate was added with 13mL of concentrated hydrochloric acid and stirred for 20 minutes. The mixture was concentrated and dried under reduced pressure at 45 ° C. 4-methyl-2-pentanone 90ml and ethanol 25mL were added. (Or dissolved), then add 225mL of n-heptane, drop to 0-5 , crystallize for 2 hours. Filter, rinse twice with cold 110mL of n-heptane to obtain off-white solid, depressurize at 45 After drying for 12 hours, dry product (2R, 3S) -2-((R) -1- (3,5-bis (trifluoromethyl) phenyl) ethoxy) -3- (4-fluorobenzene) morphine Porphyrin hydrochloride is about 42.5g, the purity of the dry product is greater than 99.5%, p- (2R, 3S) -2-((R) -1- (3,5-bis (trifluoromethyl) phenyl) ethoxy ) -3- (4-fluorobenzene) morpholine hydrochloride purification conditions for screening, see Table 1
Same Skeleton Products
Historical Records